We have been examining genes involved in the leptin signaling pathway to identify gene variants impacting body composition, with the expectation that improved understanding might help the development of precision medicine approaches for obesity (1). We are currently intensively studying a variant MC3R that is associated with adiposity in children and which appears to have functional significance for MC3R signal transduction (2). Children who are homozygous for two rare polymorphisms (Thr6Lys and Val81Ile) have significantly greater fat mass and leptin compared with wild type or heterozygous children. Recent studies have confirmed greater adiposity in homozygous adults. Ongoing studies attempt to understand the mechanisms by which these sequence alterations impact body weight. We have initiated a study comparing energy balance during adaptation to a high-fat diet in humans with double-mutant and wild type MC3R. We have also successfully bred and studied novel knock-in mice expressing the human wild type MC3R(hWT/hWT) and human double-mutant MC3R(hDM/hDM). MC3R(hDM/hDM) have greater weight and fat mass, increased energy intake and feeding efficiency, but reduced fat-free mass compared with MC3R(hWT/hWT). MC3R(hDM/hDM) mice did not have increased adipose tissue inflammatory cell infiltration or greater expression of inflammatory markers despite their greater fat mass. Serum adiponectin was increased in MC3R(hDM/hDM) mice and MC3R(hDM/hDM) human subjects. MC3R(hDM/hDM) bone- and adipose tissue-derived mesenchymal stem cells (MSCs) differentiated into adipocytes that accumulated more triglyceride than MC3R(hWT/hWT) MSCs. MC3R(hDM/hDM) impacted nutrient partitioning to generate increased adipose tissue that appeared metabolically healthy. These data confirmed the importance of MC3R signaling in human metabolism and suggested a previously-unrecognized role for the MC3R in adipose tissue development. Current studies are seeking to understand better the roles of MC3R in peripheral metabolism including studies of hepatic autophagy. We have previously found that leptin is an important predictor of weight gain in children and identified children with hyperleptinemia and leptin receptor mutations. We have also found hyperleptinemia out of proportion with body fat mass in children with psychological loss of control (LOC) over eating. Such data suggest the importance of leptin resistance as a factor stimulating weight gain and have led to recent explorations of other syndromes associated with obesity that may cause dysregulation of leptin signaling, including Bardet Biedl and Alstrm syndromes (3). Current studies are directed at understanding additional genetic, physiological, and psychological factors that place children at-risk for undue weight gain (4-10), including attentional biases (4), anxiety (6), and LOC eating (6-8). We also examined if low metabolic rate may contribute to obesity in African American children (10). Some recent initiatives have targeted insulin resistance. One trial studied the role of depressive symptoms in childrens insulin resistance. A randomized clinical trial to study the effects on insulin resistance of preventing depression in obese adolescents with a family history of type 2 diabetes found at one-year follow-up, among girls with moderate baseline depressive symptoms (N = 78), those given a cognitive behavioral therapy (CBT) program for prevention of depression developed lower 2-hr insulin than those in a health education control group (Delta-16 vs. 16 muIU/mL, P<.05). Further studies are required to determine if adolescents with moderate depression show metabolic benefits after CBT. Another series of pilot studies has tested if short bouts of activity may improve glucose tolerance in children. In non-overweight children, we found that Interrupting sitting resulted in a 32% lower insulin Area Under the Curve (AUC; P<.001), 17% lower C-peptide AUC (P<.001), and 7% lower glucose AUC (P = .018) vs continuous sitting. We have recently found similar decreases in insulin and c-peptide response to glucose challenges in children with overweight and obesity. Interrupting sedentary time with brief moderate-intensity walking thus improved short-term metabolic function. A new trial beginning in 2017 is testing if these acute improvements are sustained over 1 week. These studies may help lead to community studies examining if interrupting sedentary behavior is a promising prevention strategy for reducing cardiometabolic risk in children. Investigations concentrating on binge eating behaviors in children suggest that such behaviors are also associated with adiposity in children and predict future weight gain in children at-risk for overweight. The ability to consume large quantities of palatable foods, especially when coupled with decreased subsequent satiety, may play a role in the greater weight gain found in binge eating children. Two protocols have examined efficacy of interpersonal therapy (IPT) as a weight gain preventive strategy among children and adolescents who report binge eating behaviors (11-12). IPT was not superior to health education (HE) to prevent excess weight gain at 1- or 3-year follow-up the entire cohort (12). However, among girls with high self-reported baseline social-adjustment problems or anxiety, IPT, compared to HE, was associated with the steepest declines in BMIz (p<.001) and fat mass (p<=.03). Thus, in obesity-prone adolescent girls, IPT was associated with improvements in BMIz over 3 years among youth with high social-adjustment problems or trait anxiety. Future studies are planned to test the efficacy of IPT for obesity prevention among at-risk girls with social-adjustment problems and/or anxiety. We also have evaluated feasibility and acceptability of a preventive family-based interpersonal psychotherapy (FB-IPT) program (11). FB-IPT was compared to family-based health education (FB-HE) in 29 children, 8 to 13 years who had overweight/obesity and LOC-eating. At post-treatment, children in FB-IPT reported greater decreases in depression and anxiety and less odds of LOC-eating than FB-HE. Family-based approaches that address interpersonal and emotional underpinnings of LOC-eating in preadolescents with overweight/obesity show preliminary promise, particularly for reducing internalizing symptoms. Whether observed psychological benefits translate into sustained prevention of disordered-eating or excess weight gain requires further study. A new study is underway to examine if retraining attentional biases away from palatable foods can help children avoid weight gain. Given the rapid increase in the prevalence of obesity (16), the development of treatments for obesity is urgently needed (15). We have recently initiated additional translational trials related to modulation of the leptin signaling pathway using a melanocortin agonist called setmelanotide. Preliminary data suggest that the leptin resistance of patients with the rare obesity-causing disorder Bardet Biedl syndrome may be treatable with setmelanotide. Additional studies in other disorders that may be responsive to melanocortin agonists are underway. Finally, we have conducted studies to examine the hypothesis that administration of colchicine can decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation and will report results of a pilot clinical trial this year. Related to this study, we collaborated with the Zimmerberg laboratory to study adipose tissue biopsies obtained at baseline from adults in this trial. Analyses examining insulin-induced phosphorylation of Akt in adipose tissue samples have supported that adipose tissue insulin resistance occurs at the whole-cell level, rather than being a graded response (13).